The present invention relates to nucleic acid molecules, preferably genomic sequences, encoding an ATP-gated ion channel P2X7R which contain a mutation in the 5′UTR or 3′UTR regions, a mutation in exon 3, 5, 6, 8 or 13 or in introns 1, 3, 4, 5, 6, 7, 9, 11 or 12 or a deletion in exon 13, which allow to diagnose affective disorders. The invention further relates to polypeptides encoded by said nucleic acid molecules vectors and host cells comprising said nucleic acid molecules as well as to methods for producing polypeptides encoded by said nucleic acid molecules. The present invention also provides antibodies specifically directed to polypeptides encoded by said nucleic acid molecules and aptamers specifically binding said nucleic acid molecules.
Additionally, primers for selectively amplifying said nucleic acid molecules are provided in the present invention as well as kits, compositions, particularly pharmaceutical and diagnostic compositions comprising said nucleic acid molecules, vectors, polypeptides, aptamers, antibodies and/or primers. Moreover, the present invention relates to methods for diagnosing affective disorders associated with a non-functional P2X7R protein, an altered ATP-gating of the P2X7R protein, an over- or underexpression of the P2X7R protein or associated with the presence of any one of the aforementioned nucleic acid molecules or polypeptides encoded thereby. Additionally, the present invention relates to uses and methods for treating affective disorders employing a functional or non-functional ATP-gated ion-channel P2X7R.
The present invention also relates to uses of modulators of P2X7R activity for treating affective diseases.
Furthermore, the present invention also relates to methods for identifying and characterizing compounds which are capable of specifically interacting with or altering the characteristics of the polypeptides of the present invention as well as to methods for the production of pharmaceutical compositions.
Up to 10% of persons visiting a physician are afflicted with an affective disorder (also known as behavioural disorder, mood disorder). Nonetheless, most cases remain undiagnosed or inadequately treated. Affective disorders include among others, depression, anxiety, and bipolar disorder. These diseases are well described in the literature; see, for example, Diagnostic and Statistical Manual of Mental Disorders—4th Edition Text Revision (DMS-IV-TR), American Psychiatric Press, 2000.
Depression, also known as unipolar affective disorder, is characterized by a combination of symptoms such as lowered mood, loss of energy, loss of interest, feeling of physical illness, poor concentration, altered appetite, altered sleep and a slowing down of physical and mental functions resulting in a relentless feeling of hopelessness, helplessness, guilt, and anxiety. The primary subtypes of this disease are major depression, dysthymia (milder depression), and atypical depression. Other important forms of depression are premenstrual dysphoric disorder and seasonal affective disorder. Present treatment of depression consists of psychotherapy, antidepressant drugs, or a combination of both. Most antidepressive drugs target the transport of the neurotransmitters serotonin and/or norepinephrine, or the activity of the enzyme monoamine oxidase. They include: Selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine), tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine, nortriptyline), monoamine oxidase inhibitors (e.g., phenelzine, isocarboxazid, tranylcypromine), and designer antidepressants such as mirtazapine, reboxetine, nefazodone. However, all existing antidepressive drugs possess shortcomings such as long latency until response, high degree of non-responders and undesirable side effects (Holsboer, Biol. Psychol. 57 (2001), 47-65). Therefore, a need exists in the medical community for new antidepressive drugs with improved pharmacological profile (Baldwin, Hum. Psychopharmacol. Clin. Exp. 16 (2001), S93-S99).
Anxiety disorders are defined by an excessive or inappropriate aroused state characterized by feelings of apprehension, uncertainty, or fear. They are classified according to the severity and duration of their symptoms and specific affective characteristics. Categories include: (1) Generalized anxiety disorder, (2) panic disorder, (3) phobias, (4) obsessive-compulsive disorder, (5) post-traumatic stress disorder, and (6) separation anxiety disorder. The standard treatment for most anxiety disorders is a combination of cognitive-behavioural therapy with antidepressant medication. Additional medications include benzodiazepines and buspirone.
Bipolar disorder, also known as manic-depression, is characterized by mood swings between periods of mania (i.e. mood elevation including exaggerated euphoria, irritability) and periods of depression. Bipolar disorder is classified according to the severity of the symptoms. Patients diagnosed with bipolar disorder type I suffer from manic or mixed episodes with or without major depression. In Bipolar Disorder type II, patients have episodes of hypomania and episodes of major depression. With hypomania the symptoms of mania (euphoria or irritability) appear in milder forms and are of shorter duration. The current drugs used to treat bipolar disorders are lithium, valproate and lamotrigine, which stimulates the release of the neurotransmitter glutamate. As with antidepressive drugs, they take weeks to become effective and can result in undesirable side effects, for example, high levels of lithium in the blood can be fatal.
Compelling evidence suggest that affective disorders are biological diseases. However, there are no laboratory tests or other procedures that a common physician can use to make a definitive diagnosis. Instead, a specially trained physician or psychiatrist must diagnose the illness based on a group of symptoms that occur together. This process is often time consuming and laborious requiring several visits for the physician to perform a careful history of the symptoms that the patient is currently experiencing as well as any symptoms he or she has had in the past. Therefore, an easy and effective method for the accurate diagnosis of affective disorders is of high interest to the medical community (Wittchen et al., J. Clin. Psychiatry 62, suppl. 26 (2001), 23-28).
Most patients afflicted with affective disorders have family antecedents and identical twins studies suggest a strong genetic component. For example, genetic mapping on an isolated population of the central valley of Costa Rica suggests a locus for severe bipolar disorder at chromosome 18q22-q23 (Freimer et al., Nature Genetics 12 (1996), 436-441). Moreover, genetic studies performed on the Old Order Amish population suggest that genes on chromosomes 6, 13, and 15 may contribute to the susceptibility of bipolar affective disorder (Ginns et al., Nature Genetics 12 (1996), 431-435). Recently, a genome-wide search in a homogenous population found in the Saguenay/Lac-St-Jean region of Quebec suggests the presence of a major locus for bipolar disorder on chromosome 12q23-q24 (Morissette et al., Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88 (1999), 567-587). Susceptibility loci on chromosomes 5 and 21 were also found in this study. Other groups report minimal evidence for linkage in the region of 12q23 (Kelsoe et al., Proc. Natl. Acad. Sci. USA 98 (2001), 585-590; Sklar, Annu. Rev. Genomics Hum. Genet. 3 (2002), 371-413). Given the various loci mentioned in the above studies (e.g., links to chromosomes 5, 6, 12, 13, 15, 18, 21), a definite genetic link for affective diseases remains to be found.
Thus, although several genes have been assumed to be linked with affective disorders as mentioned hereinabove, however, no clear correlation has so far been shown. Since no well-suited medication nor diagnosis on a molecular level for affective disorders is available, there is a need for identifying a gene whose mutations cause the whole spectrum of affective disorders as well as for providing medicaments and methods for diagnosis and treatment of affective disorders.
Thus, the technical problem underlying the present invention is to provide means and methods for diagnosis and treating affective disorders.
The solution to said technical problem is achieved by providing the embodiments characterized in the claims.